The skeletal dysplasias are a heterogeneous group of disorders which result in disproportionate short stature and/or skeletal deformities. Although they have long been considered to be generalized disorders of endochondral and/or membraneous ossification, the extent of their heterogeneity has only recently been recognized and little is known concerning their pathogenesis. This project is directed toward a multidisciplinary investigation of the clinical, genetic, morphological and biochemical characteristics of the skeletal dysplasias. The specific aims of this proposal will be: a) definition of the clinical, radiographic and genetic heterogeneity of the skeletal dysplasias; b) definition of the natural history, growth characteristics and complications of each of these disorders; c) delineation of the dynamics of craniofacial growth and development in each of these disorders; d) elucidation of the histological, histochemical, and ultrastructural characteristics of chondro-osseous tissue in each of these diseases; e) detailed analysis of the collagen composition of normal human fetal and postnatal cartilage; f) elucidation of the basic biochemical defects in each of these diseases by means of biochemical analysis of cartilage and metabolic studies of cultured chondrocytes; g) identification and investigation of specific animal models of the human chondrodystrophies; h) establishment of an International Registry of Dysplastic Skeletal Tissues. This program is divided into three separate grant proposals: 1) Clinical and Morphological studies, which will attempt to delineate the clinical and radiographic characteristics of these disorders, study the morphology and ultrastructure of their chondro-osseous tissue and identify and investigate specific animal models of these human disorders; 2) Collagen Polymorphism of Human Cartilage which will attempt to characterize the new varieties of collagen found in human cartilage and investigate their distribution and age related changes; and 3) Biochemical Studies of the Chondrodystrophies, which will attempt to define the molecular defects of chondrodystrophic cartilage components and characterize each of these aberrations.